The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal untreatable neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). TSE pathogenesis involves the accumulation of an abnormal misfolded protein, called PrPres, in infected hosts. In FY 2013: 1) We have collaborated with extramural investigators to identify a designed Trpzip-3 &#946;-hairpin that inhibits amyloid formation in two different amyloid systems. 2) We have continued to search for new anti-prion compounds from libraries of novel compounds that have been synthesized in Brazil by our collaborators. A number of new compounds have been identified that block PrP-res formation and have other attractive characteristics, but further testing of these compounds will be required to better establish their therapeutic potential.